ANXIETY AND COMORBID MENTAL DISORDERS
| FACILITATING TREATMENT FOR ANXIOUS PATIENTS WITH COMORBID MENTAL ILLNESS —Peter P.
Roy-Byrne, MD, Professor and Vice-Chair, Department of Psychiatry and Behavioral Sciences, University of Washington
School of Medicine, and Chief of Psychiatry, Harborview Medical Center, Seattle
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| Introduction: how much of poor outcome in patients due to failure to deliver treatments effectively and how much
to resistance to treatment? anxiety disorder rarely occurs alone; comorbidity affects facilitation of treatment by affecting
recognition of anxiety disorder, psychoeducation of patient, selection of treatment, and assessment of outcome
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| Comorbidities that affect treatment outcome in anxiety disorders: most important are bipolar illness, major
depression, substance abuse, medical illness, and personality disorder; sometimes difficult to sort out anxiety
disorder from comorbidities
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| Bipolar illness and anxiety: when bipolar illness presents as treatment-refractory anxiety, anxiety may not be episodic,
although there may be episodic depression superimposed on anxious or agitated background; there may be history
of insomnia and/or overstimulation with antidepressants, perhaps leading patient to prefer benzodiazepines; axis
2 cluster B features may be present; there may be history of depression in childhood or adolescence; manic or mixed
equivalent includes anxiety, irritability, ruminative racing-like thinking, difficulty with sleep initiation, and low-level
impulsivity
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| Social anxiety disorder (SAD): some cases of SAD may represent subgroup of bipolar-spectrum disorders; these
patients improve while taking antidepressants, but present in hypomanic state; without antidepressant, symptoms of
social anxiety return; may be less desirable to give these patients antidepressants, using instead mood stabilizer, anticonvulsant,
or benzodiazepine
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| Major depression may obscure recognition of SAD and posttraumatic stress disorder (PTSD): when
it occurs comorbidly, major depression can dominate clinical picture of SAD and PTSD because their symptoms
less often overtly manifested as agitation, anxiety, or panic; compared to patients with panic and generalized anxiety
disorder (GAD), patients with SAD and PTSD infrequently present for treatment and often come to clinical attention
only when they develop depression
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| PTSD and avoidance of treatment: patients with PTSD particularly difficult to engage in treatment and often do
not seek treatment; comorbid PTSD in patients with depression results in substantial increase in discharges against
medical advice (AMA)
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| Substance abuse and anxiety: which is primary problem? does patient try to self-medicate anxiety by abusing
substance or is anxiety secondary to substance abuse? does not matter, both must be treated simultaneously and
vigorously
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| Anxiety and major medical disorders: National Comorbidity Study showed patients with anxiety had higher
rates of all medical illnesses that study considered (hypertension, arthritis, asthma, gastrointestinal disorder, ulcer,
autoimmune disease, and neurologic disorders) than patients without anxiety; in older patients, medical illness frequent
cause of anxiety symptoms
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| Anxiety and personality disorder: anxiety as symptom prominent in many patients with personality disorders;
should anxiety be target of treatment? if anxiety symptoms improved with treatment, would personality disorder improve?
or if personality disorder not addressed as primary problem, would anxiety symptoms worsen? is borderline
personality disorder complex PTSD? (study suggested that untreated anxiety disorder may cause some PTSD-like
symptoms that would improve with treatment of personality disorder)
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| Treatment of anxiety disorder: data indicate that in community practices, patients with anxiety disorder very unlikely
to receive evidence-based treatment; speaker posits that this is due as much to poor delivery of treatment as
to resistance to treatment; to remedy problem, clinician must know which treatments have evidence to support
them and know how to deliver those treatments, and patient must “buy into” need for treatment and be willing to
adhere to treatment regimen
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| How does psychoeducation vary with comorbidity? bipolar patients must take medication and endorse, at
least in part, medical model of their illness; anxious patients with major depressive disorder who want cognitive-behavioral
therapy (CBT) may need more complex “tailored” CBT; substance abuse and dependence contraindicate
use of benzodiazepines and may enhance opportunity to use motivational interviewing for treatment of both; medical
illness may increase patient’s sensitivity to side effects and complicate medication interactions (these patients may
be more open to nonmedical treatments); personality disorder must be vigorously addressed or relatively ignored
while anxiety addressed, but personality disorder must be considered as major factor limiting patient’s engagement
in treatment
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| Treating anxious patients: anxious patients less likely to perceive need for treatment; targets for maximizing anxious
patient’s engagement in treatment—beliefs and knowledge (what has happened to patient and family in past
and how has this shaped their beliefs and knowledge?); patient’s preferences (what kind of treatment does patient
prefer and can this be changed by discussion and/or negotiation?); motivation and readiness to change; significant
others (what do significant others think about treatment offered to patient?)
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| Benzodiazepines: in patients with GAD and depressive symptoms, benzodiazepines may exacerbate depression;
little data for patients with PTSD, but 1 study showed people who received benzodiazepine shortly after trauma had
more PTSD symptoms than control group at 6-mo follow-up; before writing prescription for benzodiazepine, consider
1) is busy clinician using benzodiazepine as substitute for therapeutic encounter? 2) would patient feel less
need for immediate symptom relief if clinician spent time “setting the stage” for treatment?
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| Medical illness affects treatment of anxiety by: altering patient’s motivation to seek, accept, and adhere to
specific kinds of treatment; increasing sensitivity to side effects; complicating treatment regimens; potentially creating
medication interactions
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| Other treatment modalities: chronic life stressors affect treatment of panic, anxiety, “and a number of other areas”;
if patient pharmacologically oriented, suggest that alternative forms of treatment (eg, psychotherapy) may be
more appropriate as primary treatment or as adjunct to medications; studies show that individuals in low-income
bracket have poor response to treatment in general (low income is proxy for other kinds of chronic stress, eg, familial
stress, dangerous neighborhoods, poor social support, poor interpersonal relationships); disturbed spousal and
family relationships predict poor response
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| Cognitive behavioral therapy: might enhance engagement of some patients because 1) it is brief; 2) it is goal-directed
and symptom-focused; 3) outcomes are monitored; 4) problem and process of change can be modeled; 5) patient
and physician collaborate; elements of CBT include providing information, cognitive restructuring, exposure,
and teaching skills for symptom management
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| Behavioral activation: defined as procedures to activate patients so they expose themselves to positive events,
minimize avoidance and rumination, and learn through experience that they feel better because of this
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| Combined treatment: ideally should have clear rationale for both modalities, have clear treatment goals for both
modalities, and tailor therapeutic approach to individual patient
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| Conclusions: while anxiety symptoms often prominent in clinical presentation, they may obscure or divert attention
from important comorbidities; conversely, anxiety disorders sometimes obscured by more prominent and persistent major
depression or medical illness; consideration of comorbidities should inform clinician’s psychoeducation of patient,
selection of treatment, ongoing assessment of outcome, and adjustment of treatment; however, no evidence exists that
efficacy of anxiety treatments varies with comorbidity
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| USE OF SECOND-GENERATION ANTIPSYCHOTICS IN ANXIETY AND DEPRESSION —David E. Adson,
MD, Associate Professor, Department of Psychiatry, and Director, Ambulatory Research Center, University of Minnesota
Medical School, Minneapolis
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| Introduction: no second-generation antipsychotic has Food and Drug Administration (FDA) approval for use in
unipolar depression or anxiety disorders; olanzapine-fluoxetine combination has FDA indication for bipolar depression
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| Treatment resistance: defined as ≤25% improvement in symptoms in clinical practice, ≤50% in clinical trials; in
trials, outcomes measured by standardized interviews; remission defined as improvementof ≥25% in symptoms or
score of ≤7 on Hamilton Depression Rating Scale (HAM-D); several scales available for measuring treatment resistance
after 6 wk of treatment
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| Problems with residual symptoms: more physical and emotional disability; higher rates of recurrence of primary
disorder; more comorbidity (including substance abuse); higher utilization of medical services
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| Current options available to address treatment-resistant depression (TRD): most practitioners start treatment
of depression with selective serotonin reuptake inhibitor (SSRI); if treatment resistance occurs, options include
switching to different SSRI, switching to selective norepinephrine reuptake inhibitor (SNRI), adding SNRI, augmenting
SSRI with bupropion, lithium, thyroid hormone, or pindolol, using vagus nerve stimulation (VNS) or electroconvulsive
therapy (ECT), and administering psychotherapy
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| Why use second-generation antipsychotics in TRD? first-generation antipsychotics block dopamine-2 (D2 )
receptor; second-generation antipsychotics have some effect in blocking D2 but also block serotonin receptors,
which modulates some side effects of dopamine blockade alone; first-generation antipsychotics show utility in treating
depression and anxiety, but have many extrapyramidal side effects (eg, akathisia, parkinsonism) unacceptable to
patients; in addition to D2 blockade, all second-generation antipsychotics are 5-HT2 antagonists, plus ziprasidone
(Geodon) and aripiprazole (Abilify) are 5-HT1A agonists, ziprasidone and risperidone (Risperdal) are 5-HT1D agonists,
ziprasidone inhibits reuptake of norepinephrine and serotonin, and aripiprazole is partial D2 agonist
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| Study results: olanzapine (Zyprexa)—shown to be effective when added to fluoxetine (Prozac) and when combination
of fluoxetine plus olanzapine (Symbyax) added to venlafaxine; risperidone—in small trial, when risperidone
added to SSRI, all patients had remission of depressive symptoms in <1 wk; in larger trial, when
risperidone given with fluoxetine, 76% had remission, 17% had response; in still larger trial, when risperidone
added to citalopram (Celexa), response rate 59%; adverse events included headache, dry mouth, nausea, and increased
appetite; no akathisia observed; fourth trial added risperidone to fluvoxamine and found remission rate
76% and response rate 17%; quetiapine (Seroquel)—speaker’s study recruited patients on SSRI for 6 wk who
still had anxiety symptoms; by second week, anxiety symptoms reduced 50% and depressive symptoms improved
50%; side effects included dry mouth, constipation (which tended to resolve over time), sedation, and
weight gain; no patients dropped out due to side effects
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| Why study anxiety and depression together? commonly coexist (60% of patients with major depressive disorder
also have anxiety disorder); presence of both associated with increased symptoms, prolonged course, and worse
outcome; clinical presentation and treatment often similar (antidepressant usually first-line treatment, whether patient
depressed or anxious)
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| Other studies: GAD and major depression—clinically very similar; when ziprasidone added to SSRI, 50% responded
and 25% achieved remission, but many dropped out due to side effects (eg, fatigue, sleep problems, restlessness);
when aripiprazole added to SSRI, 80% of subjects had >50% reduction in anxiety and depressive
symptoms by second week, but 50% experienced akathisia when dose of aripiprazole increased from 5 mg to 10
mg
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| Second-generation antipsychotics not benign drugs: potential adverse events include neuroleptic malignant
syndrome and tardive dyskinesia; increased mortality rate found in elderly patients with dementia-related psychosis;
patients may develop hypoglycemia and diabetes (speaker recommends monitoring blood glucose, serum lipid profile,
and, in some cases, hemoglobin A1c , and calculating body mass index and measuring waist circumference); side
effects include sedation, weight gain, and postural hypotension)
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 | Other considerations: second-generation antipsychotics expensive; drug interactions possible with inhibitors and
inducers of oxidative metabolism; tobacco smoking affects serum levels of second-generation antipsychotics; no
clear data to support use of >1 antipsychotic at a time; are alternative treatments for anxiety that bad (eg, literature
shows that majority of people who take benzodiazepines remain compliant with dosage, do not escalate use,
and do not abuse benzodiazepines)? in 1999, 70% of antipsychotic prescriptions written for off-label uses, percentage
has probably risen since then
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Educational Objectives
| The goal of this program is to educate the listener about treating anxiety when it occurs with other mental illnesses.
After hearing and assimilating this program, the clinician will be better able to:
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| 1. Discuss how much of poor outcome in treating anxiety and comorbid mental disorders is due to failure to deliver
treatments effectively and how much is due to treatment resistance.
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| 2. Explain the relationships between anxiety and certain mental illnesses and how those relationships affect treatment.
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| 3. Determine the best treatment for anxiety with comorbid mental illness.
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| 4. Describe the differences between first-generation and second-generation antipsychotics.
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| 5. Compare the advantages and disadvantages of using second-generation antipsychotics to augment antidepressants
in patients with comorbid anxiety and depression.
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Discussed on This Program
Aripiprazole [Abilify]
Bupropion hydrochloride [Wellbutrin , Wellbutrin SR, Wellbutrin XL, Zyban]
Citalopram hydrobromide [Celexa]
Divalproex sodium [Depakote]
Duloxetine [Cymbalta]
Fluoxetine hydrochloride [Prozac, Sarafem]
Fluvoxamine maleate
Gabapentin [Neurontin]
Lamotrigine [Lamictal]
Levothyroxine sodium (T4 , L-thyroxine) [Levothroid, Levoxyl, Synthroid, Thyro-Tabs, Unithroid ]
Liothyronine sodium (T3 ) [Cytomel, Triostat]
Lithium [Eskalith, Eskalith CR, Lithobid, Lithonate, Lithotabs] )
Olanzapine [Zyprexa]
Olanzapine and fluoxetine hydrochloride [Symbyax]
Pregabalin [Lyrica]
Quetiapine fumarate [Seroquel]
Risperidone [Risperdal]
Venlafaxine hydrochloride [Effexor]
Ziprasidone hydrochloride [Geodon]
Suggested Reading
Adson DE et al: Preliminary experience with adjunctive quetiapine in patients receiving selective serotonin reuptake
inhibitors. Depress Anxiety 19:121, 2004; Adson DE, Kushner MG, Fahnhorst TA: Treatment of residual
anxiety symptoms with adjunctive aripiprazole in depressed patients taking selective serotonin reuptake
inhibitors. J Affect Disord 86:99, 2005; Akiskal HS: The dark side of bipolarity: detecting bipolar depression in its
pleomorphic expressions. J Affect Disord 84:107, 2005; Blier P, Szabo ST: Potential mechanisms of action of
atypical antipsychotic medications in treatment-resistant depression and anxiety. J Clin Psychiatry 66(Suppl 8):30,
2005; Debattista C: Augmentation and combination strategies for depression. J Psychopharmacol 20(3 Suppl):11,
2006; Devarajan S, Dursun SM: Olanzapine plus venlafaxine in treatment-resistant depression. J Psychopharmacol
19:434, 2005; Holtzheimer PE 3rd et al: The impact of comorbid posttraumatic stress disorder on short-
term clinical outcome in hospitalized patients with depression. Am J Psychiatry 162:970, 2005; Ishak WW, Rapaport
MH, Gotto JG: The effectiveness of atypical antipsychotic medications in depressive disorders. Curr Psychiatry
Rep 6:422, 2004; MacKinnon DF et al: Bipolar disorder and panic disorder in families: an analysis of
chromosome 18 data. Am J Psychiatry 155:829, 1998; Means-Christensen AJ et al: In search of mixed anxiety-
depressive disorder: a primary care study. Depress Anxiety Mar 1; [Epub ahead of print], 2006; Means-
Christensen AJ et al: Using five questions to screen for five common mental disorders in primary care: diagnostic
accuracy of the Anxiety and Depression Detector. Gen Hosp Psychiatry 28:108, 2006; Nemeroff CB: Use of atypical
antipsychotics in refractory depression and anxiety. J Clin Psychiatry 66(Suppl 8):13, 2005; Ros S et al: Potentiation
strategies for treatment-resistant depression. Acta Psychiatr Scand Suppl 2005:14; Shelton RC et al:
Olanzapine/fluoxetine combination for treatment-resistant depression: a controlled study of SSRI and nortriptyline
resistance. J Clin Psychiatry 66:1289, 2005; Stewart SA et al: Discussion: using benzodiazepines in clinical practice.
J Clin Psychiatry 66(Suppl 2):39, 2005; Valenca AM et al: Do social-anxiety-disorder patients belong to a bipolar-spectrum
subgroup? J Affect Disord 86:11, 2005; Young AS et al: The quality of care for depressive and
anxiety disorders in the United States. Arch Gen Psychiatry 58:55, 2001.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. For this issue,
Dr. Roy-Byrne reported that he has received grants/research support from GlaxoSmithKline, Pfizer, and Forest Laboratories;
was a consultant/advisor to Alza, Cephalon, GlaxoSmithKline, Forest Laboratories, Eli Lilly Co., Janssen,
Jazz, Pfizer, Pharmacia, Roche, and Wyeth-Ayerst; and received speaking honoraria from GlaxoSmithKline, Forest
Laboratories, Novartis, Pfizer, Pharmacia, and Wyeth-Ayerst. Dr. Adson reported that he has received research support
or speaking honoraria from AstraZenica, Bristol-Myers-Squibb, Cyberonics, Eli Lilly Co., Forest Laboratories,
GlaxoSmithKline, and Pfizer.
Dr. Roy-Byrne was recorded at the 11th Annual Psychopharmacology Update, presented February 16-19, 2006, in
Las Vegas, NV, and sponsored by the American Psychiatric Association and the Nevada Psychiatric Association. Dr.
Adson was recorded at An Entertaining and Eclectic Elucidation of Psychiatric Erudition, held September 19-20,
2005, in Minneapolis, MN, and sponsored by the Department of Psychiatry, Continuing Medical Education, University
of Minnesota Medical School. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation
in the production of this program.
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